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The development, maintenance, and destruction of cartilage are regulated by mechanical factors throughout life. Mechanical cues in the cartilage fetal endoskeleton influence the expression of genes that guide the processes of growth, vascular invasion, and ossification. Intermittent fluid pressure maintains the cartilage phenotype whereas mild tension (or shear) promotes growth and ossification. The articular cartilage thickness is determined by the position at which the subchondral growth front stabilizes. In mature joints, cartilage is thickest and healthiest where the contact pressure and cartilage fluid pressure are greatest. The depth-dependent histomorphology reflects the local fluid pressure, tensile strain, and fluid exudation. Osteoarthritis represents the final demise and loss of cartilage in the skeletal elements. The initiation and progression of osteoarthritis can follow many pathways and can be promoted by mechanical factors including: (1) reduced loading, which activates the subchondral growth front by reducing fluid pressure; (2) blunt impact, causing microdamage and activation of the subchondral growth front by local shear stress; (3) mechanical abnormalities that increase wear at the articulating surface; and (4) other mechanically related factors. Research should be directed at integrating our mechanical understanding of osteoarthritis pathogenesis and progression within the framework of cellular and molecular events throughout ontogeny.

Objective This study tested the hypothesis that intermittent hydrostatic pressure applied to human osteoarthritic chondrocytes modulates matrix metalloproteinase and pro-inflammatory mediator release in vitro . Design Human osteoarthritic articular chondrocytes were isolated and cultured as primary high-density monolayers. For testing, chondrocyte cultures were transferred to serum-free medium and maintained without loading or with exposure to intermittent hydrostatic pressure (IHP) at 10MPa at a frequency of 1Hz for periods of 6, 12 and 24h. Levels of matrix metalloproteinase-2, -9 (MMP-2, -9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and the pro-inflammatory mediators, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), released into the culture medium were assessed by ELISA. Matrix metalloproteinase activity was confirmed by zymographic analysis. Results In the absence of IHP, levels of MMP-2, TIMP-1, IL-6, and MCP-1 in the chondrocyte culture medium increased in a time-dependent manner. Application of IHP decreased MMP-2 levels at all time periods tested, relative to unloaded control cultures maintained for the same time periods. Although 84/82kDa bands were faintly detectable by zymography, MMP-9 levels were not quantifiable in medium from loaded or unloaded cultures by ELISA. TIMP-1 levels were not altered in response to IHP at any time period tested. IL-6 and MCP-1 levels decreased in cultures exposed to IHP at 12 and 24h, relative to unloaded control cultures maintained for the same time periods. Conclusion IHP decreased release of MMP-2, IL-6 and MCP-1 by osteoarthritic chondrocytes in vitro suggesting that pressure influences cartilage stability by modulating chondrocyte expression of these degradative and pro-inflammatory proteins in vivo .

Objective. The objective of this study was to quantify the effect of collar geometry on stress transfer and micromotion in idealized models of a cementless implant having an intramedullary stem. Background. Intramedullary stems exist on several types of orthopaedic implants, including the femoral component of hip arthroplasties and segmental replacements used in the surgical treatment of a tumor or trauma in the diaphysis of a long bone. Methods. Using three-dimensional finite element analysis, we compared four idealized, straight-stemmed, axisymmetric prostheses: flat-collared (0°), conical-collared (30° and 60°), and collarless tapered (80°). We simulated axial and non-axial (20° oblique) loads as well as non-ingrown and ingrown interface conditions. Results. Without bone ingrowth, stress transfer to bone adjacent to the collar increased with collar angle. Micromotion at the distal stem increased moderately with collar angle from 0° through 60°, then increased markedly from 60° to 80°. With simulated bony ingrowth, the effect of the collar was greatly reduced. Conclusions. The results of this study suggest that the selection of collar angle represents a tradeoff between initial stress transfer and micromotion. Stems with conical collar angles in the range of 30–60° can provide increased stress transfer compared to a flat collar design and reduced micromotion compared to a collarless tapered design. Relevance This study suggests that a conical-collared stem has the potential to better maintain bone density and achieve stable fixation. This finding is consistent with clinical data and indicates that further biomechanical and clinical investigations may be in order.

Wear particles generated after total joint arthroplasty activate monocyte/macrophages and incite formation of a granulomatous periprosthetic tissue associated with bone loss and implant loosening. This study tested the hypothesis that selective opsonization of orthopedic implant biomaterial wear particles by human serum proteins influences monocyte/macrophage activation. Serum protein binding to metallic, polymeric, and ceramic particles was determined by one-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Individual proteins bound to particles were subsequently identified using two-dimensional SDS-PAGE, microsequencing techniques, and SWISS-PROT analysis. Effects of selective protein opsonization on particle-induced monocyte/macrophage activation were assessed by quantification of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha release. Results from one-dimensional gel analyses revealed distinct serum protein-binding patterns specific for each material tested. Two-dimensional gel analysis together with amino acid sequencing of the prominent protein species confirmed the presence of albumin and alpha-1-antitrypsin bound to all particles tested. In contrast to the metallic particles, apolipoprotein was a major species associated with polymeric particles. Opsonization of PMMA particles with purified preparations of each of the identified proteins showed that albumin significantly enhanced particle-induced monocyte/macrophage activation. These data confirm orthopedic biomaterial specific binding of human serum proteins and demonstrate that albumin exacerbates particle-induced monocyte/macrophage activation. Alterations in the chemical and surface properties of orthopedic biomaterials to modulate protein interactions may improve implant longevity.

Patients with anterior cruciate ligament instability resulting from incomplete tears or elongation in continuity without ligament detachment historically have been treated conservatively or by graft replacement. The literature is sparse regarding alternative treatments. The current study presents experience using monopolar thermal repair on 28 consecutive knees with partial anterior cruciate ligament tears all symptomatically unstable. All lesions were less than 6 months old (average, 77 days; range, 7-180 days) and with a difference of 6 mm or more (average, 9 mm; range, 6-13 mm) when comparing both knees using KT-1000 evaluation. Incomplete tears of the anterior cruciate ligament were seen at arthroscopic evaluation. The rehabilitation protocol included use of a brace for at least 6 weeks and progressive weightbearing. A 2-year minimum followup (range, 24-35 months) was done in all patients following the International Knee Documentation Committee guidelines. The overall outcome was normal or nearly normal in 96% of the patients. One failure occurred at 8 weeks. Twenty-six knees had a KT-1000 difference between 0 and 2 mm (average, 1.9 mm). Because thermal application causes death to some of the cells directly treated, it should be taken into account in selection and application. Immediately after thermal use, the anterior cruciate ligament, although thicker and tighter, is at first weaker than normal. Rehabilitation and compliance are critical during early ligament healing. This procedure seems to be a reasonable alternative to anterior cruciate ligament grafting in selected patients.

Complications in total knee arthroplasty directly related to hardware failure other than polyethylene wear are rare. We report 2 cases of symptomatic screw migration into the joint space from total knee prostheses. In the first case, a screw disengaged from a constrained condylar knee prosthesis. Arthroscopy using standard arthroscopy portals and a small arthrotomy were performed to remove the screw. In the second case, symptomatic screw disengagement and posterior migration from the tibial component of a posterior-stabilized prosthesis occurred. Revision with replacement of the polyethylene insert and locking screw was required. Copyright 2002, Elsevier Science (USA). All rights reserved.

Mechanical loading alters articular cartilage metabolism. However, mechanisms underlying intracellular signaling and communication between cells in response to mechanical stresses remain enigmatic. This study tested the hypothesis that shear stress-induced nitric oxide (NO) production participates in the regulation of matrix protein gene expression. The data presented here demonstrate that exposure of human osteoarthritic chondrocytes to a continuously applied shear stress (1.64 Pa) upregulated NO synthase gene expression and increased NO release by 1.8-, 2.4-, and 3.5-fold at 2, 6, and 24 h, respectively. Exposure of chondrocytes to a short duration of shear stress for 2 h resulted in the release of accumulation of NO in the culture medium. Exposure of chondrocytes to shear stress for 2, 6, and 24 h inhibited type II collagen mRNA signal levels by 27%, 18% and 20% after a constant post-shear incubation period of 24 h. Aggrecan mRNA signal levels were inhibited by 30%, 32% and 41% under identical conditions. Addition of an NO antagonist increased type II collagen mRNA signal levels by an average of 1.8-fold (137% of the un-sheared control) and reestablished the aggrecan mRNA signal levels by an average of 1.4-fold after shear stress (92% of the un-sheared control) (ANOVA p < 0.05). These data support the hypothesis that shear stress-induced NO release may influence the development of degenerative joint diseases by inhibiting matrix macromolecule synthesis.

A review of postoperative infected anterior cruciate ligament reconstructions was done on 3500 consecutive arthroscopic procedures. The purpose was to assess incidence, diagnosis, treatment, and outcome factors. Six postoperative in-traarticular infections were detected. Average followup was 3 years (range, 2-8 years). The rate of infection was 0.14%. Five men and one woman with a median age of 32.5 years (range, 20-51 years) comprised the study group. The average interval from the onset of symptoms to the initial arthroscopic intervention was 7.5 days (range, 2-20 days). Staphylococcus aureus was present in three knees, Staphylococcus epidermidis in two, and Streptococcus nonhemolytic in one. All patients had initial arthroscopic debridement and lavage followed by 6 weeks of intravenous antibiotics. Two grafts were removed: one patient had delayed ligament reconstruction and the other had total knee arthroplasty. The remaining patients had full range of motion. In the group with the best result, two patients had Staphylococcus epidermidis and one had Staphylococcus aureus, which was treated 2 days after clinical symptoms began. The other two patients infected with Staphylococcus aureus had unsatisfactory results. Anterior cruciate ligament infection is rare, but diagnosable. When treated early with appropriate antibiotic therapy and arthroscopic debridement, four of six grafts were retained. If the infection does not respond rapidly to early therapy, then graft removal is an option.

Periprosthetic tissues observed at sites of loose total joint implants exhibit abundant macrophages, lymphocytes, fibroblasts and particulate debris. Macrophages phagocytose orthopaedic debris and release proinflammatory cytokines, chemokines, matrix metalloproteinases and other substances. In addition, other cell types present in tissues harvested from the bone-implant interface are thought to influence periprosthetic bone resorption. The present study examined the effects of polymethylmethacrylate (PMMA), cobalt chrome molybdenum alloy (CoCr), and titanium-alloy particle challenge on macrophages co-cultured with lymphocytes in vitro. Potential synergistic effects of lymphocytes on macrophage activation were determined by measuring interleukin-6 and tumor necrosis factor-alpha release following exposure to orthopaedic biomaterial particles. Exposure of macrophages or macrophages co-cultured with lymphocytes to all three types of particles resulted in increased release of interleukin-6 and tumor necrosis factor-alpha at 48 h, when compared to macrophages or macrophages co-cultured with lymphocytes, respectively, cultured in the absence of particles. Lymphocytes isolated from periprosthetic tissues secreted increased basal levels of cytokines relative to peripheral blood lymphocytes. Higher doses of PMMA and titanium-alloy particles stimulated increased levels of cytokine release in the macrophage and macrophage/lymphocyte groups. In contrast, a higher dose of CoCr particles (0.075% v/v) was not as effective as the 0.015% v/v dose, indicating probable CoCr toxicity. The macrophage/lymphocyte co-culture did not show synergism between the two types of cells with respect to cytokine release. T-cells at the bone-implant interface may alter the biological response to particulate debris.

Orthopaedic wear debris induces release of bone-resorbing factors from macrophages and fibroblasts. However, the extent to which elemental metallic particles induce bone cells to express factors contributing to implant loosening remains unclear. This study showed that exposure of MG-63 osteoblast-like cells to titanium particles at a concentration of 0.30% v/v resulted in a 15-fold increase in IL-6 release into the culture medium after 24 hours, when compared with cells without particles. Northern blots revealed that exposure of MG-63 cells to titanium particles at a concentration of 0.30% v/v for 24 hours increased IL-6 mRNA signal levels by 9.6-fold, when compared with control cultures. Pretreatment of MG-63 cells with cytochalasin B prevented the particle-induced increase of IL-6 expression but did not alter the basal level of IL-6 release from cells cultured in the absence of particles. The protein kinase C inhibitor, H7, and the serine/threonine kinase inhibitor, genistein, abolished the particle-induced increase in IL-6 release at a concentration of 100 microM for each compound. In contrast, an inhibitor of protein kinase A, HA1004, had no effect on the particle-induced increase in IL-6 release. The transcription factors, nuclear factor IL-6 and nuclear factor kappa B, translocated into the nucleus within 1 hour of particle exposure. This study showed that osteoblast-like cells respond to titanium particles through increased expression of the proinflammatory cytokine, IL-6, in a process requiring phagocytosis and intracellular signaling pathways. These results suggest that osteoblasts play a direct role in implant loosening because of localized release of soluble mediators such as interleukin-6.

Background: Loosening of the implant after total joint arthroplasty remains a serious problem. The activation of macrophages by wear debris from implants, mediated by the release of cytokines that elicit bone resorption, may lead to loosening. The purpose of the present study was to elucidate the mechanisms of macrophage activation by titanium particles from the components of implants and to identify the signaling pathways involved in particle-mediated release of cytokines. Methods: Macrophages were isolated from mononuclear leukocytes obtained from healthy human donors and were exposed to titanium-alloy particles that had been obtained from periprosthetic membranes collected at revision total joint arthroplasties and then enzymatically prepared. The experimental protocols included examination of the effects of the inhibition of phagocytosis and the binding of antibodies to macrophage complement receptors on particle-induced macrophage activation. The release of the proinflammatory cytokines TNF-α (tumor necrosis factor-alpha) and IL-6 (interleukin-6) was used to assess macrophage activation. The signaling pathways involved in the induction of cytokine release were analyzed by identification of phosphorylated proteins with use of the Western blot technique and by translocation of the transcription factors nuclear factor-kappa B (NF-κB) and nuclear factor-interleukin-6 (NF-IL-6) into the nuclear protein fraction with use of electrophoretic mobility shift assays. The role of serine/threonine and tyrosine kinase pathways in the activation of nuclear factors and the release of cytokines was examined with use of selective pharmacological agents. Results: Exposure of macrophages to titanium-alloy particles in vitro for forty-eight hours resulted in a fortyfold increase in the release of TNF-α and a sevenfold increase in the release of IL-6 (p < 0.01). Phagocytosis of particles occurred in approximately 73 percent of the macrophages within one hour of exposure. Pretreatment of the macrophages with cytochalasin B reduced phagocytosis by 95 percent but did not reduce the release of TNF-α or IL-6. Thus, phagocytosis of particles was not necessary for induction of the release of TNF-α or IL-6 in the cultured macrophages. Ligation of the macrophage CD11b/CD18 receptors by integrin-specific antibodies also increased the release of TNF-α and IL-6. Antibodies to CD11b/CD18 receptors (macrophage Mac-1 receptors) reduced phagocytosis of particles by 50 percent (p < 0.05). (The CD11b/CD18 macrophage receptor is the macrophage receptor for the complement component CR3bi. The CD11b/CD18 macrophage receptor can also bind to ICAM-1 and ICAM-2. CD is the abbreviation for cluster of differentiation, and ICAM is the abbreviation for intercellular adhesion molecule.) Inhibition of phagocytosis was not accompanied by a decrease in the release of TNF-α and IL-6. Blocking RNA synthesis with actinomycin D or preventing protein synthesis with cycloheximide abolished or decreased particle-induced release of TNF-α and IL-6 from the macrophages. Macrophage release of TNF-α and IL-6 in response to particles coincided with increased tyrosine phosphorylation and mitogen-activated protein kinase activation. Inhibition of tyrosine and serine/threonine kinase activity decreased the particle-induced release of cytokines. Exposure of macrophages to either titanium-alloy particles or to antibodies to the receptor proteins CD11b and CD18 for thirty minutes activated the transcription factors NF-κB and NF-IL-6. Inhibition of particle phagocytosis did not block activation of the transcription factors. However, inhibition of tyrosine and serine/threonine kinase activity decreased the activation of NF-κB and NF-IL-6. Conclusions: These data suggest that particle-induced macrophage release of TNF-α and IL-6 does not require phagocytosis but is dependent on tyrosine and serine/threonine kinase activity culminating in activation of the transcription factors NF-κB and NF-IL-6. Clinical Relevance: Retrieval studies have documented numerous macrophages in association with particulate debris in granulomatous tissue surrounding failed total joint replacements. However, the molecular basis on which wear particles induce macrophage expression of proinflammatory cytokines and bone-resorbing factors remains unclear. This in vitro study showed that particles incite the release of proinflammatory cytokines from macrophages in the absence of phagocytosis. These results imply that contact of wear particles with macrophage cell-surface membrane proteins, such as the complement receptor CD11b/CD18, is sufficient signal for release of proinflammatory cytokines. The data further suggest that release of proinflammatory cytokines follows transmission of a membrane recognition event through intracellular signaling pathways that effect gene activation and protein synthesis. Therefore, these data indicate that a reduction in the formation of wear particles can be expected to improve the outcome after total joint arthroplasty by decreasing macrophage activation.

Postoperative knee flexion in patients undergoing Insall-Burstein-II total knee arthroplasty at 2 years was evaluated regarding two basic questions: what groups of patients gain or lose the most flexion and what groups of patients have the best or worst postoperative flexion. Thirteen preoperative variables (maximum flexion, flexion arc, tibiofemoral angle, quadriceps strength, extensor lag, Knee Society score, Knee Society patient assessment, gender, age, height, weight, diagnosis, and surgeon) and four postoperative variable (leg length change, tibiofemoral angle, distance from patella to the joint line, and the tibial prosthesis anteroposterior translation on a lateral radiograph) were used in an attempt to explain postoperative flexion. The analysis was performed on 164 consecutive Insall-Burstein-II total knees in which the data were gathered prospectively on a time oriented medical record database. A regression tree analysis was used to identify several groups of patients, characterized by preoperative factor values, who had markedly above average performance on postoperative flexion. The preoperative factors identified include preoperative flexion, flexion arc, tibiofemoral angle, extensor lag, diagnosis, and age. The only postoperative variable of significance was tibiofemoral angle. Among the potential determinants of postoperative flexion that failed to appear predictive were the Knee Society scores and surgeon. Preoperative flexion is known to be a critical determinant of postoperative flexion in total knee replacement. However, in the current study, preoperative flexion accounted for only half of the difference between the best (122 degrees) and the worst (88 degrees) group, as determined with regression tree analysis.

The purpose of this study was to characterize the cell types (using immunohistochemistry) and cytokine expression (using in situ hybridization) of tissues surrounding well fixed and loose cemented prostheses undergoing revision. Clinical and radiographic data were gathered prospectively for a series of cemented total joint replacements undergoing revision. Three groups were identified: (1) loose implants with osteolysis (10 specimens), (2) loose implants without osteolysis (11 specimens), and (3) well fixed implants (7 specimens). At surgery, a specimen was harvested from the bone cement interface. Immunohistochemical staining was performed using monoclonal antibodies to identify macrophages and lymphocyte subgroups. Human antisense probes were selected to identify the mRNA for specific cytokines using in situ hybridization. The percentage of positively staining cells was determined for each antibody or probe using a grid counting technique. Tissues from loose cemented prostheses with osteolysis contained significantly greater numbers of macrophages and T lymphocytes compared with tissues from loose and well fixed cemented prostheses without osteolysis. The number of interleukin-1 and interleukin-6 positive cells was highest in specimens with osteolysis and lowest in specimens from well fixed prostheses. These cytokines modulate the growth and differentiation of cells in the immune system and the monocyte and macrophage system and mediate the remodeling of bone and mesenchymal tissues. Specific cell populations and cytokine profiles appear to be involved in periprosthetic osteolysis; this information may be useful in planning strategies for prevention and treatment.

Expression of matrix metalloproteinase-9 mRNA in osteoarthritic and normal cartilage was analyzed using reverse transcription-polymerase chain reaction and in situ hybridization. Fifty-four osteoarthritic cartilage samples were obtained from 24 patients undergoing total knee arthroplasty. Sixteen normal cartilage samples were obtained from non-osteoarthritic knees of four autopsy cases. With normal cartilage, reverse transcription-polymerase chain reaction analysis for matrix metalloproteinase-9 mRNA showed that chondrocytes exhibited only a trace signal. In analysis of osteoarthritic cartilage, chondrocytes of moderately and severely fibrillated cartilage exhibited a 73-fold and 110-fold increase in matrix metalloproteinase-9 mRNA signal, respectively, relative to normal cartilage. Chondrocytes of nonfibrillated osteoarthritic cartilage exhibited a 6-fold increase (p < 0.02) in matrix metalloproteinase-9 mRNA signal relative to normal cartilage. Analysis of matrix metalloproteinase-9 mRNA expression in fresh-frozen sections of normal and osteoarthritic cartilage by in situ hybridization confirmed these results. This study showed that reverse transcription-polymerase chain reaction provides a sensitive index of mRNA levels in normal and osteoarthritic cartilage samples and suggests that increased expression of matrix metalloproteinase-9 precedes fibrillation of cartilage in the development of osteoarthritis.

The pneumatic tourniquet produces ischemic changes in limbs. The effects of tourniquet release on systemic blood pressure and metabolic parameters were studied in 11 adult patients undergoing total knee replacement under general anesthesia. Mean arterial pressure (MAP) decreased rapidly after the release of the tourniquet, becoming significant at 3 min and remaining significantly depressed up to 15 min post release. Arterial pH, PaO2, PaCO2, lactate acid, and potassium changed significantly after the release, but normalized within 30 min. These results are notably different from a previous study in a similar patient population undergoing knee replacement under epidural anesthesia. Compared to patients under epidural anesthesia, patients receiving general anesthesia with mechanical ventilation are unable to compensate for the metabolic load caused by the tourniquet release, as the latter group are unable to alter their ventilatory rate. In elderly patients with decreased cardio-pulmonary reserve, this may be of clinical importance.

This report presents a method for analyzing matrix metalloproteinase-9 (92 kD gelatinase) MMP-9 mRNA expression using reverse transcription polymerase chain reaction (RT-PCR). With this method, chondrocytes isolated from small samples of osteoarthritic cartilage showed significantly elevated signal for MMP-9 mRNA compared to normal cartilage. In addition, cells of synovial fluid samples aspirated from osteoarthritic joints also exhibited MMP-9 expression using this technique. RT-PCR proved to be a sensitive method for assessing MMP-9 regulation in osteoarthritic and normal cartilage, and may provide a useful index of arthritic cartilage and synovial fluid cell metabolism when limited tissue is available.

This study tested the effects of fluid-induced shear on high density monolayer cultures of adult articular chondrocytes. Fluid-induced shear (1.6 Pa) was applied by cone viscometer to normal human and bovine articular chondrocytes for periods of 24, 48, and 72 hours. At 48 and 72 hours, fluid-induced shear caused individual chondrocytes to elongate and align tangential to the direction of cone rotation. Fluid-induced shear stimulated glycosaminoglycan synthesis by 2-fold (p < 0.05) and increased the length of newly synthesized chains in human and bovine chondrocytes. In human chondrocytes, the hydrodynamic size of newly synthesized proteoglycans also was increased. After 48 hours of fluid-induced shear, the release of prostaglandin E2 from the chondrocytes was increased 10 to 20-fold. In human chondrocytes, mRNA signal levels for tissue inhibitor of metalloproteinase increased 9-fold in response to shear compared with the controls. In contrast, mRNA signal levels for the neutral metalloproteinases, collagenase, stromelysin, and 72 kD gelatinase, did not show such major changes. This study demonstrated that articular chondrocyte metabolism responds directly to physical stimulation in vitro and suggests that mechanical loading may directly influence cartilage homeostasis in vivo.

The objective of this study is to determine a protocol for collecting acid-fast bacilli (AFB) and fungal intraoperative cultures during orthopedic procedures. An observational study was undertaken. Four hundred forty-six AFB cultures and 486 fungal cultures were processed over a 2-year period. The number of positive cultures was determined. A protocol specific to handling these types of specimens was developed. Cost analysis was completed to determine both the time and money saved if the new protocol was implemented. The infrequency of positive AFB and fungal cultures in this study suggests that it is only necessary to routinely request AFB and fungal cultures on 1 of 5 samples. Implementation of this protocol has potential to lead to substantial cost reduction and resource savings without diminishing patient outcomes.

This study tested the hypothesis that physiologic tendon loading modulates the fibrous connective tissue phenotype in undifferentiated skeletal cells. Type I collagen sponges containing human bone marrow stromal cells (MSCs) were implanted into the midsubstance of excised sheep patellar tendons. An ex vivo loading system was designed to cyclically stretch each tendon from 0 to 5% at 1.0 Hz. The MSC-sponge constructs were implanted into 2 tendon sites: the first site subjected to tension only and a second site located at an artificially created wrap-around region in which an additional compressive stress was generated transverse to the longitudinal axis of the tendon. The induced contact pressure at the wraparound site was 0.55 +/- 0.12 MPa, as quantified by pressure-sensitive film. An MSC-sponge construct was maintained free swelling in the same bath as an unloaded control. After 2 h of tendon stretching, the MSC-sponge constructs were harvested and real-time PCR was used to quantify Fos, Sox9, Cbfa1 (Runx2), and scleraxis mRNA expression as markers of skeletal differentiation. Two hours of mechanical loading distinctly altered MSC differentiation in the wrap-around region and the tensile-only region, as evidenced by differences in Fos and Sox9 mRNA expression. Expression of Fos mRNA was 13 and 52 times higher in the tensile-only and wrap-around regions, respectively, compared to the free-swelling controls. Expression of Sox9 mRNA was significantly higher (2.5-3 times) in MSCs from the wraparound region compared to those from the tensile-only region or in free-swelling controls. In contrast, expression levels for Cbfa1 did not differ among constructs. Scleraxis mRNA was not detected in any construct. This study demonstrates that the physiologic mechanical environment in the wrap-around regions of tendons provides stimuli for upregulating early response genes and transcription factors associated with chondrogenic differentiation. These differentiation responses begin within as little as 2 h after the onset of mechanical stimulation and may be the basis for the formation of fibrocartilage that is typically found in the wrap-around region of mature tendons in vivo.

This study examined the effects of intermittent hydrostatic pressure (IHP) and transforming growth factor-beta 3 on chondrogenesis of adult human mesenchymal stem cells (hMSCs) in vitro. Chondrogenic gene expression was determined by quantifying mRNA signal levels for SOX9, a transcription factor critical for cartilage development and the cartilage matrix proteins, aggrecan and type II collagen. Extracellular matrix production was determined by weight and histology. IHP was applied to hMSCs in pellet culture at a level of 10 MPa and a frequency of 1 Hz for 4 h per day for periods of 3, 7, and 14 days. hMSCs responded to addition of TGF-beta 3 (10 ng/mL) with a greater than 10-fold increase (p0.01) in mRNA levels for each, SOX9, type II collagen, and aggrecan during a 14-day culture period. Applying IHP in the presence of TGF-beta 3 further increased the mRNA levels for these proteins by 1.9-, 3.3-, and 1.6-fold, respectively, by day 14. Chondrogenic mRNA levels were increased with just exposure to IHP. Extracellular matrix deposition of type II collagen and aggrecan increased in the pellets as a function of treatment conditions and time of culture. This study demonstrated adjunctive effects of IHP on TGF-beta 3-induced chondrogenesis and suggests that mechanical loading can facilitate articular cartilage tissue engineering.

Range of motion after total knee arthroplasty is an important variable in determining clinical outcome. The goal of this study was to assess range of motion across five types of posterior-stabilized knee prostheses used sequentially in the same institution during 17 years. The hypothesis was that absolute flexion would improve in newer models of this basic prosthesis design. Only primary knee arthroplasties in patients with osteoarthritis were evaluated. A retrospective analysis was done. Three hundred fifty-eight knees with osteoarthritis were reviewed. The average arc of motion was 103 degrees before surgery and 111 degrees after surgery. Absolute flexion was clinically similar but improved from before surgery (110 degrees ) to after surgery (113 degrees ). No difference was found when comparing improvements in range of motion among the different types of prostheses used. This study did not show that any knee system made a difference in determining the final range of motion postoperatively. Height emerged as a predictive factor of absolute flexion. Preoperative range of motion is the most important variable in determining improvements in range of motion, with height playing a secondary role.Prognostic study, Level II-1.

A consecutive series of 49 patients who had a primary total hip arthroplasty (THA) for osteoarthritis is reviewed to determine the differences in clinical outcome between the direct lateral and the posterior surgical approaches to the hip. Group 1 comprised 28 patients who had THA by the same surgeon using a posterolateral approach. Group 2 comprised 21 patients who had THA using the direct lateral approach, modified from Hardinge. The improvement in the limp, abductor strength, Trendelenburg test, and range of motion over time was similar in the two groups. The average Harris hip score at 1 year was 90 for Group 1 (posterior approach) and Group 2 (lateral approach). At 2-year minimum follow up, the Harris hip score was 94 for both groups. Radiographic review showed that the incidence and severity of heterotopic bone was also similar for both groups. The authors conclude that the clinical and radiographic outcome for THA using the posterior and the lateral approaches to the hip yield similar clinical results.

Matrix metalloproteinases are a family of endopeptidases that collectively degrade all components of the extracellular matrix at neutral pH. During the progression of arthritis, MMPs mediate the degradation of cartilage, which consists largely of Type II collagen fibrils and proteoglycans. The collagenases, a subgroup of MMPs, have the singular ability to cleave intact collagens and may provide a rate-limiting step in cartilage destruction. In arthritic lesions, collagenase-1 (matrix metalloproteinase-1) and collagenase-3 (matrix metalloproteinase-13) mediate the irreversible destruction of cartilage, suggesting that these enzymes are therapeutic targets. We describe the role of metalloproteinases in the destruction of connective tissues in arthritis and the treatment strategies that have been developed to block matrix metalloproteinases in an attempt to prevent this destruction. We also discuss novel compounds that may selectively inhibit these cartilage-degrading enzymes, providing opportunities to develop new therapeutic approaches.

The treatment of osteoarthritis includes a wide spectrum of approaches. This article reviews current practices in medical, pharmaceutical and surgical treatment with a perspective toward the immediate, distant and far distant future. At present, with the exception of surgery, all other treatments are palliative. That is to say that many of these treatments relieve pain and increase function. However, on the basis of medical evidence, these treatments do not change the course of the disease. Surgical interventions, including joint replacement and osteotomy, reverse the progress of osteoarthritis and provide long-term improved function and pain relief for specific joints. The goal of treating osteoarthritis is to arrest and reverse its progress regionally or globally through biologic methodology. Meaningful progress for biologic intervention accumulates annually. Pluripotent mesenchymal cells can be coaxed into chondrocytes or stem cells. Cytokines, growth factors, chemokines, protease inhibitors, kinases, apoptosis, mechanics, and genetics are increasingly recognized to play key roles in the control of the articular cartilage behavior. Knowledge of their roles and relationships advance toward solutions related to osteoarthritis. In the future, biologic control may be harnessed to regrow joints or limbs, as currently occurs naturally in newts and salamanders. Fortunately, until then we have ever improving joint replacement.

Homeostasis of articular cartilage depends in part on mechanical loads generated during daily activity whereas inappropriate joint loads result in focal degeneration of cartilage, as occurs in osteoarthritis. We will review results of a series of questions regarding the effects of two types of mechanical loads-intermittent hydrostatic pressure and shear stress-on adult human articular chondrocytes in high-density monolayer culture. Intermittent hydrostatic pressure increased aggrecan and Type II collagen gene expression in normal chondrocytes and induced changes in the cell-associated proteins of normal and osteoarthritic chondrocytes. Hydrostatic pressure also counteracted inhibitory effects of bacterial lipopolysaccharide on matrix protein expression by cultured chondrocytes. Application of shear stress to osteoarthritic chondrocytes increased the release of the proinflammatory mediator, nitric oxide, decreased aggrecan and Type II collagen expression, and induced molecular changes associated with apoptosis whereas hydrostatic pressure increased matrix macromolecule expression. The findings show that the types of load comprising the mechanical loading environment of articular cartilage considerably alter chondrocyte metabolism and suggest that mechanical stimulation may be used for in vitro or in vivo approaches for cartilage engineering.

Background: Primary total hip replacement performed through an incision that is ≤10 cm in length has been advocated as a minimally invasive technique. Proponents have claimed that mini-incision techniques reduce blood loss, transfusion requirements, postoperative pain, and the length of the hospital stay compared with standard techniques through a longer incision. However, we are aware of no well-designed comparison study that supports these claims. The purpose of the present study was to compare the short-term results of a mini-incision with a standard incision technique for total hip replacement. Methods: A consecutive series of patients who underwent 135 primary unilateral total hip replacements (fifty with use of a mini-incision [≤10 cm] and eighty-five with use of a standard incision) by three surgeons at one hospital were studied. Each surgeon selected patients to have a mini-incision procedure and performed a standard approach in the remaining patients. A posterior approach was used for all procedures. In-hospital data were collected retrospectively, and the initial postoperative radiographs were analyzed. Because of the selection process, the patients who had a mini-incision had both a significantly lower average body-mass index (p = 0.008) and a lower average score on the American Society of Anesthesiologists rating (p = 0.006), indicating that they were thinner and healthier than the patients who had a standard incision. Results: With the numbers of patients available, no significant differences were found between the groups with respect to the average surgical time, intraoperative blood loss, in-hospital transfusion rate, length of hospital stay, or the patients' disposition after discharge. The mini-incision group was found to have a significantly higher risk of a wound complication (p = 0.02), a higher percentage of acetabular component malposition (p = 0.04), and poor fit and fill of femoral components inserted without cement (p = 0.0036). Conclusions: There was no evidence that the mini-incision technique resulted in less bleeding or less trauma to the soft tissues of the hip, factors that would have produced a quicker recovery and a shorter hospital stay, than did the standard technique. The present study, which was based on the authors' initial experience with the mini-incision technique, failed to confirm the positive clinical outcomes reported by previous uncontrolled cohort studies, and the findings suggest that further analysis of this new technique is needed before it can be recommended for general use. Level of Evidence: Therapeutic study, Level III-2 (retrospective cohort study). See Instructions to Authors for a complete description of levels of evidence.

VEGF and VEGF receptor, Flt-1, expression was observed in periprosthetic tissues surrounding loosened total joint implants. Exposure of monocyte/macrophages to titanium particles resulted in increased VEGF expression, p44/42 MAPK activation, and VEGF-dependent macrophage chemotaxis. Increased levels of angiogenic factors, such as VEGF, may be critically important in wear debris-induced implant loosening after total joint arthroplasty. Introduction: Periprosthetic osteolysis after total hip arthroplasty occurs in association with formation of a vascularized granulomatous tissue in response to particulate debris. Materials and Methods: This study examined expression of vascular endothelial growth factor (VEGF) and the VEGF receptor in 10 periprosthetic tissues from loosened prostheses and quantified effects of titanium particles on VEGF release, intracellular signaling, and VEGF-dependent chemotaxis in primary cultures of human monocyte/macrophages. Results: Double immunofluorescent staining showed that VEGF and Flt-1 co-localized with cells positive for the macrophage marker, CD11b, in the periprosthetic tissues. Monocyte/macrophages challenged with titanium particles showed a dose- and time-dependent release of VEGF ranging from 2.8- to 3.1-fold and exhibited increased expression of VEGF121 and VEGF165 mRNAs, reaching levels up to 5.0- and 8.6-fold, respectively, by 48 h (p < 0.01). Exposure of monocyte/macrophages to titanium particles upregulated phosphorylated-p44/42 mitogen-activated protein kinase (MAPK) within 30 minutes. Particle-induced activation of p44/42 MAPK and release of VEGF were dose-dependently suppressed by pretreatment of cells with PD98059, a specific inhibitor of p44/42 MAPK. Monocyte/macrophages challenged with titanium particles also showed a time-dependent activation of AP-1, a transcription factor associated with VEGF expression (p < 0.01). Supernatants from particle-challenged monocyte/macrophages increased macrophage chemotactic activity by 30%, which was significantly inhibited by anti-VEGF neutralizing antibody (p < 0.01). Conclusions: This study suggests that induction of VEGF release from monocyte/macrophages in response to orthopaedic biomaterial wear debris may contribute to periprosthetic osteolysis and implant loosening.

Onset and progression of cartilage degeneration is associated with shear stress occurring in diarthrodial joints subjected to inappropriate loading. This study tested the hypothesis that shear stress induced nitric oxide is associated with altered expression of regulatory onco-proteins, bcl-2, and Fas (APO-1/CD95) and apoptosis in primary human osteoarthritic chondrocyte cultures. Shear stress induced membrane phosphatidylserine and nucleosomal degradation were taken as evidence of chondrocyte apoptosis. Application of shear stress upregulated nitric oxide in a dose-dependent manner and was associated with increases in membrane phosphatidylserine and nucleosomal degradation. Increasing levels of shear stress decreased expression of the anti-apoptotic factor, bcl-2, from 44 to 10 U/ml. Addition of the nitric oxide antagonists, L-N(5)-(1-iminoethyl) ornithine and Nomega-nitro-L-arginine methyl ester (L-NAME), reduced shear stress induced nucleosomal degradation by 62% and 74%, respectively. Inhibition of shear stress induced nitric oxide release by L-NAME coincided with a 2.7-fold increase of bcl-2, when compared to chondrocytes exposed to shear stress in the absence of L-NAME. These data suggest that shear stress induced nitric oxide is associated with changes in apoptotic regulatory factors that alter chondrocyte metabolism and may contribute to joint degeneration.

To test the effects of intermittent hydrostatic pressure (IHP) on nitric oxide (NO) release induced by shear stress and matrix macromolecule gene expression in human osteoarthritic chondrocytes in vitro.Chondrocytes isolated from cartilage samples from 9 patients with osteoarthritis were cultured and exposed to either shear stress or an NO donor. Nitrite concentration was measured using the Griess reaction. Matrix macromolecule mRNA signal levels were determined using reverse-transcriptase polymerase chain reaction and quantified by imaging analysis software.Exposure to shear stress upregulated NO release in a dose and time-dependent manner. Application of IHP inhibited shear stress induced NO release but did not alter NO release from chondrocytes not exposed to shear stress. Shear stress induced NO or addition of an NO donor (sodium nitroprusside) was associated with decreased mRNA signal levels for the cartilage matrix proteins, aggrecan, and type II collagen. Intermittent hydrostatic pressure blocked the inhibitory effects of sodium nitroprusside but did not alter the inhibitory effects of shear stress on cartilage macromolecule gene expression.Our data show that shear stress and IHP differentially alter chondrocyte metabolism and suggest that a balance of effects between different loading forces preserve cartilage extracellular matrix in vivo.

This study addressed the hypothesis that duration and magnitude of applied intermittent hydrostatic pressure (IHP) are critical parameters in regulation of normal human articular chondrocyte aggrecan and type II collagen expression. Articular chondrocytes were isolated from knee cartilage and maintained as primary, high-density monolayer cultures. IHP was applied at magnitudes of 1, 5 and 10 MPa at 1 Hz for durations of either 4 h per day for one day (4 x 1) or 4 h per day for four days (4 x 4). Total cellular RNA was isolated and analyzed for aggrecan and type II collagen mRNA signal levels using specific primers and reverse transcription polymerase chain reaction (RT-PCR) nested with beta-actin primers as internal controls. With a 4x1 loading regimen, aggrecan mRNA signal levels increased 1.3- and 1.5-fold at 5 and 10 MPa, respectively, relative to beta-actin mRNA when compared to unloaded cultures. Changing the duration of loading to a 4x4 regimen increased aggrecan mRNA signal levels by 1.4-, 1.8- and 1.9-fold at loads of 1, 5 and 10 MPa, respectively. In contrast to the effects of IHP on aggrecan, type II collagen mRNA signal levels were only upregulated at loads of 5 and 10 MPa with the 4x4 loading regimen. Analysis of cell-associated protein by western blotting confirmed that IHP increased aggrecan and type II collagen in chondrocyte extracts. These data demonstrate that duration and magnitude of applied IHP differentially alter chondrocyte matrix protein expression. The results show that IHP provides an important stimulus for increasing cartilage matrix anabolism and may contribute to repair and regeneration of damaged or diseased cartilage.

The role of continuous passive motion (CPM) in the management of septic arthritis and inflammatory arthritis remains of interest. CPM produces cyclic variations in intraarticular pressure that facilitates transport of fluid, nutrients, and solutes within and/or across the joint and stimulates chondrocyte metabolism. However, the precise mechanisms mediating the responses of chondrocytes to joint motion remain unclear. This study tested the hypothesis that dynamic mechanical loading counteracts effects of bacterial lipopolysaccharide (LPS), an inflammatory mediator, on chondrocyte metabolism. Intermittent hydrostatic pressure (IHP) (10 MPa for 4 h) was applied to human chondrocytes pretreated with LPS (1 microg/ml for 18 h). LPS activation of chondrocytes decreased mRNA signal levels of type II collagen by 67% and aggrecan by 56% and increased nitric oxide by 3.1-fold, monocyte chemotactic protein-1 mRNA signal levels by 6.5-fold, and matrix metalloproteinase-2 mRNA signal levels by 1.3-fold. Application of IHP to LPS-activated chondrocytes decreased nitric oxide synthase mRNA signal levels and nitric oxide levels in the culture medium. Exposure of LPS-activated chondrocytes to IHP upregulated type II collagen and aggrecan mRNA signal levels by 1.7-fold, relative to chondrocytes activated by LPS and maintained without loading. In addition, application of IHP decreased the upregulation in signal levels of monocyte chemotactic factor-1 and matrix metalloproteinase-2 following LPS activation by 45% and 15%, respectively. These data show that mechanical loading counteract effects of inflammatory agents, such as bacterial LPS, and suggest that postinfection sequelae are influenced by the presence or absence of joint loading.

Harris-Galante modular acetabular components (Zimmer, Warsaw, IN) have been used widely for primary and revision total hip arthroplasties. The survivorship of this implant has been well documented in the literature. Failure of the liner locking mechanism and subsequent dissociation of the polyethylene liner from the metal-backed shell is a potential cause of failure, however. We report 7 cases of liner dissociation and propose the mode of failure. The result in all cases was a well-fixed metal acetabular shell with a failed locking mechanism, which usually is managed by revision of the entire component. This procedure may be accompanied by the potential loss of acetabular bone stock, which should be replenished.

Perioperative knee mechanics currently are evaluated Perioperative knee mechanics currently are evaluated by measuring range of motion. This is an incomplete measurement, however, because the torque applied to achieve the motion is not measured. We hypothesized that a custom goniometer and force transducer could measure the torque required to passively flex a knee through its full range of motion. This measurement was done in the operating room immediately before and after surgery in 20 knees having total knee arthroplasty and 9 having surgery on another limb. Surgery changed the mechanics of 8 knees, whereas unoperated knees remained unchanged. This measurement technique is safe, easy, and repeatable. It improves on the current standard of perioperative knee measurement and can be applied to investigate the effects of surgery and rehabilitation on ultimate knee motion.

This study analysed MIF mRNA and protein expression in human macrophages exposed in vitro to polymethylmethacryate and titanium alloy particles. MIF levels released from macrophages without exposure to particles were in the range of 2-4 ng/ml. Exposure of macrophages to particles as demonstrated increased MIF release at 0.075%-0.225% v/v particle concentration, which was maximal at 12-24 h. MIF mRNA signal levels in cells with and without particles at a concentration of 0.075% showed no significant differences in a time course experiment. The profile of MIF release in response to increasing particle concentration coincided with increased release of lactate dehydrogenase. The viability of the cells was unchanged by the addition of particles as determined by 3H-thymidine uptake. These data suggest that MIF expression may represent an independent macrophage response to locally high particle concentrations. (C) 2000 Academic Press.

Osteoarthritis is a disease in which articular cartilage metabolism is altered, leading to cartilage destruction. As insulin-like growth factor-I (IGF-I) is the major anabolic mediator for articular cartilage, and the IGF-binding proteins (IGFBPs) are an integral part of the IGF axis, they may play a role in the pathophysiology of osteoarthritis. Chondrocytes isolated from fibrillated and normal appearing areas of osteoarthritic human cartilage and from normal cartilage were studied for IGF and IGFBP expression. IGF and IGFBP messenger ribonucleic acids were analyzed by a RT-quantitative PCR technique and Northern blotting. In osteoarthritic chondrocytes, IGF-I message was increased 3.5-fold, IGFBP-3 was increased 24-fold, and IGFBP-5 was increased 16-fold over normal chondrocytes. Chondrocytes from normal appearing areas of cartilage from osteoarthritic joints had intermediate levels. Message levels for beta-actin, IGF-II, and IGFBP-4 were unchanged between the cartilage types. IGF and IGFBP production were analyzed by Western ligand blots and RIAs of conditioned medium from cartilage cultured in serum-free conditions. IGF-I was undetectable in conditioned medium from normal cartilage and increased in that from osteoarthritic cartilage. Osteoarthritic cartilage samples produced IGFBP-2, -3, and -4; glycosylated IGFBP-4; and IGFBP-5. IGFBP-2, -3, and -5 production was increased in osteoarthritic cartilage. Proteases with activity against IGFBP-3 and -5 were also produced by osteoarthritic cartilage. The observation that IGFBP-3 and -5 expression and production are elevated in osteoarthritic cartilage suggests that they may be acting as a competitor for IGF-I in osteoarthritic cartilage, thus reducing the anabolic stimulation of this tissue and contributing to the net loss of cartilage in this disease.

This study tested the effect of fluid-induced shear on interleukin-6 expression in normal human articular chondrocytes in vitro. As determined by Northern blot analysis, interleukin-6 mRNA expression occurs in chondrocytes from osteoarthritic cartilage but not in normal chondrocytes. Applying fluid-induced shear stress to primary high density cultures of chondrocytes increased interleukin-6 mRNA signal 4-fold at 1 hour and 10 to 15-fold at 48 hours compared with unsheared control cultures. At 48 hours, fluid-induced shear stress increased interleukin-6 protein levels in the culture medium 9 to 10-fold compared with unsheared controls. mRNA signals for interleukin-1alpha, interleukin-1beta, and tumor necrosis factor-alpha in RNA from sheared or control chondrocytes were not detected by Northern blotting. Transforming growth factor-beta mRNA signal was detectable but was not affected by shear. In contrast, human lung fibroblasts (WI-38) responded to fluid-induced shear with increased signal for transforming growth factor-beta, but not interleukin-6, mRNA. Both cell types did respond to interleukin-1alpha with increased interleukin-6 mRNA signal. These data demonstrated that distortional forces, such as fluid-induced shear stress, alter interleukin-6 levels in normal chondrocytes in vitro and suggest that increased interleukin-6 expression in osteoarthritic cartilage may result, in part, from alterations in the mechanical loading of the tissue.

The authors have used computer modeling techniques to examine stress-related bone changes in the acetabular region. Using a previously developed theory for bone development and adaptation, the authors simulated the distribution of bone density in the natural pelvis as well as changes in bone density following total hip arthroplasty. The geometry of the finite element model was based on a two-dimensional slice through the pelvis. Starting from a solid, homogeneous structure, the computer simulations predicted the distribution of bone density throughout the natural pelvis. The predicted bone density distribution in this first simulation agreed well with the actual bone density distribution only when loads representing multiple activities were incorporated. Using the predicted density distribution as a starting point the authors modified the finite element models to study two designs of noncemented, metal-backed acetabular cups. The simulations with fully fixed bone-implant interfaces predicted extensive loss of bone density medial and inferior to the prosthetic components. The simulations with loose interfaces led to more moderate losses of bone density, indicating a load transfer more similar to that which occurs in the natural joint. The differences in simulated bone remodeling between the two component designs were quite minimal. These results indicate that acetabular components with full bony ingrowth may induce significant stress-related bone remodeling due to a nonphysiologic transfer of load.

Human articular cartilage released significantly increased levels of metal-dependent enzymes capable of degrading collagen, casein, and gelatin at a neutral pH following exposure to a sterile, purified fraction of Staphylococcus aureus culture medium. Neutral metalloprotease activity was determined by radiolabeled substrate assays and substrate gel analysis. The enzymes were activated with 4-aminophenylmercuric acetate and were inhibited by 1, 10-phenanthroline and ethylenediamine tetraacetic acid. Protein immunoblots demonstrated that type I collagenase and stromelysin (matrix metalloproteinase III) secretion was increased following staphylococcal medium challenge. The profile of enzymatic activity induced by staphylococcal medium was directly comparable to that observed with interleukin-1, which was used as a positive control. The staphylococcal medium had no inherent proteolytic activity. Increased production of the neutral metalloproteases collagenase and stromelysin may significantly contribute to the extensive cartilage destruction noted in staphylococcal septic arthritis.

Computer simulations of bone remodeling in response to mechanical stresses can be used to understand normal growth and development of the skeleton or to predict the remodeling of bone in response to prosthetic devices. Using a previously derived bone maintenance theory, a technique for computing bone density distributions was applied to the proximal femur and tibia using two-dimensional, multiple-loading finite element models. The models initially represented solid, homogeneous structures. Using an iterative bone remodeling technique that relates bone apparent density to loading history, the internal distributions of apparent density and elastic modulus for the normal bones were predicted. The finite element models were then modified to represent bones in which porous-coated femoral surface replacements and tibial tray components had been implanted. The same iterative remodeling method was then applied to predict the distribution of bone around these components. The predicted bone density distributions for the natural femur and tibia agree with previously documented normal bone morphology. The predicted bone density distributions around various implanted prostheses were characteristic of the component under investigation and were consistent with clinical and experimental findings of other investigators. In the femoral head, stress shielding occurred underneath the metal surface replacement cup, resulting in lower densities in the femoral head. The addition of a central femoral cup fixation peg caused bone hypertrophy around the peg. In the tibia, the stress concentrations around the pegs also resulted in denser bone, with a concomitant decrease in bone density at more peripheral locations underneath the prosthetic tray. This remodeling technique has the potential to be an important tool in predicting the possible remodeling consequences of new implant design features.

The outcome of total joint arthroplasty is determined by biological events at the bone-implant interface. Macrophages phagocytose implant or wear debris at the interface and release proinflammatory mediators such as interleukins 1 and 6, tumor necrosis factor-alpha, and prostaglandin E2. These mediators are thought to contribute to the resorption of periprosthetic bone. Previous studies of tissues harvested from the bone-implant interface of failed orthopaedic implants demonstrated a possible role for two other cytokines, granulocyte-macrophage colony-stimulating factor and interleukin-4. The present study examined the effects of in vitro challenge with polymethylmethacrylate particles on the expression of granulocyte-macrophage colony-stimulating factor by primary human monocytes/macrophages and the role of interleukin-4 in regulating this expression. The polymethylmethacrylate particles caused a dose-dependent release of granulocyte-macrophage colony-stimulating factor at 48 hours. This release was accompanied by increased expression of interleukins 6 and 1beta and tumor necrosis factor-alpha. Release of the lysosomal enzyme hexosaminidase also increased in response to the particles. Interleukin-4 inhibited the expression of granulocyte-macrophage colony-stimulating factor, interleukin-6, and tumor necrosis factor-alpha at 48 hours in a dose-dependent manner. The data presented in this study confirm the hypothesis that interleukin-4 downregulates particle-induced activation of macrophages, as demonstrated by the decreased release of proinflammatory mediators.

We calculated subchondral deformations and stresses in the femoral head and acetabulum during weight bearing using finite element models. Areas of high joint contact pressures on the femoral head were shown to correspond to high hydrostatic compression in subchondral bone. The magnitude of the subchondral bone compressive hydrostatic stress correlated with cartilage thickness and was highest in the superior femoral head and moderate at the acetabular roof. The seldom contacting surfaces of the medial-inferior and peripheral areas of the femoral head and the roof of the acetabulum had lower hydrostatic compression and significant subchondral bone tensile strains tangential to the joint surface. Initial cartilage fibrillation and osteophyte formation are often found in these areas. These findings suggest that fluctuating hydrostatic pressure inhibits vascular invasion and the degeneration and ossification of articular cartilage. The generation of tensile strain may promote the degenerative process by direct mechanical mechanisms. Additionally, since tensile strains are associated with a reduction in the compressive hydrostatic stresses in the cartilage and an increase in shear stresses, their presence may permit or promote vascular invasion, cartilage degeneration, and osteophyte formation. These mechanical principles in arthrosis are the same as those that have been previously demonstrated to guide the degeneration and ossification of the cartilage primordium during skeletal morphogenesis. In this sense, arthrosis may be viewed as the final stage in the degeneration and ossification of the cartilage anlage.

Cefoxitin was administered to 47 patients on an orthopedic service; 1 or 2 g of the drug was given intravenously every 4-8 hr. Thirty-one evaluated patients with acute or chronic infections of bone, joint, or muscle and tendon had an overall rate of cure of 84%. Ten patients with spinal cord injuries who had urinary tract infections due to Serratia or indole-positive Proteus were treated, and all 10 were cured. Significant adverse effects of cefoxitin included one case of fever due to the drug and three cases of superinfection. Cefoxitin therapy was successful in a variety of difficult-to-treat infections, including some of polymicrobial etiology.

Analytical and experimental studies were performed to examine some characteristics of poly(methyl methacrylate) bone cement in the context of total hip replacement. Proceeding from fundamental principles of balance of energy and heat conduction, three simulation models of total hip replacement, using the finite-element method of numerical analysis, were used to predict the temperature response in the femoral prosthesis, cement, cancellous bone, and bone-cement interface. When cement collars are a centimeter or less in thickness, the models predict little likelihood of permanent bone thermal necrosis. In addition, laboratory experimental results indicate that peak temperatures attained in Simplex-P and Palacos-R cement specimens are nearly identical and that adding 0.5 and 1.0 g of the antibiotic gentamicin to Palacos-R has negligible influence on peak temperature. Experimental results also indicate that cooling cement specimens to 8 degrees C extends the set time, which in turn could significantly increase the likelihood of stem-cement loosening during surgery.

Four in vitro human knee specimens have been loaded, two with varus-valgus femoral rotations and two with internal and external axial tibial rotations. Each specimen has been tested in full extension and in 30° of flexion. All orthogonal components of applied force and moment required to cause the rotations were measured as were all resultant orthogonal components of load on the femur. Curves fit to the data were studied to establish the portions of the applied load transmitted by each ligament.

The purpose of this study was to test whether cartilage serves as the source or repository of antigenic components active in the stimulation of inflammation in rheumatoid arthritis through an analysis of peripheral blood lymphocyte proliferation. Articular cartilage samples were obtained from patients with osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis undergoing joint replacement surgery. Each sample was homogenized and characterized biochemically with respect to the content of proteoglycan, collagen, and immunoglobulin. Proteoglycan content of rheumatoid cartilage was reduced by 71% when compared to osteoarthritic cartilage; the proteoglycan content of ankylosing spondylitis cartilage was reduced by 40% when compared to osteoarthritic cartilage. Immunoglobulins were detectable in all cartilage samples when analyzed by ELISA or end-plate titration. Lymphocyte proliferation, quantified by uptake of 3H-thymidine, was unaltered by addition of cartilage fragments, low (saline) and high salt extracts (2.0 M CaCl2), or cartilage residues. Both autologous and heterologous lymphocytes were tested against the cartilage samples with no difference in reactivity. Purified bovine articular proteoglycans and Type II collagen were also inactive. Although tetanus toxoid and phytohemagglutinin were effective stimulants of proliferation, lymphocytes from arthritis patients were suppressed relative to those of normal individuals. Analysis of arthritic articular cartilage by these techniques failed to demonstrate the presence of antigen(s) stimulating proliferation of peripheral blood lymphocytes.

An axisymmetric finite element code was used to predict stresses and displacements in the proximal tibia of the human knee. Joint geometries were determined from a midfrontal section of a normal lateral tibial plateau. Constitutive relations, tibiofemoral forces and joint contact areas were estimated from the literature. Fourier expansions were used to provide localized loading over the assumed contact region. The results emphasize that subchondral trabecular bone serves to transmit the large loads applied to the cartilage surface by gradually concentrating these loads into the compact bone of the tibial diaphysis. The model predicts a nearly hydrostatic stress state in articular cartilage within the contact region and high tensile principal strains at the edge of the contact region. For trabecular bone, the model predicts maximum compressive stresses beneath the center of the contact region and maximum shear stresses beneath the edge of the contact region. The predicted principal stress directions in the continuum representation for trabecular bone also bear a strong resemblance to the trabecular architecture of the lateral tibial plateau.

Fatigue tests to failure of compact bovine bone specimens were conducted at five stress amplitudes (65–108 MN/m2) and four temperature levels (21–45°C). The resulting relationships between fatigue life and stress amplitude, bone temperature, and bone density have been reported (Carter and Hayes, 1975). In the present study, the bone specimens were categorized into four microstructure groups based on the extent of secondary Harversian remodeling. A significant correlation (P < 0·001) between density and microstructure group was shown with primary bone specimens generally being more dense than secondary Haversian specimens. A positive correlation (P < 0·01) between fatigue life and density was revealed within each structural group. In addition, a negative correlation (P < 0·001) between fatigue life and the extent of Haversian remodeling was shown even after appropriate adjustments for density differences. These data suggest that Haversian remodeling of primary bovine bone reduces fatigue resistance not only by decreasing bone density, but also by creating an inherently weaker structure.

Eleven patients with intractable rheumatoid arthritis were treated with total lymphoid irradiation. After radiotherapy, there was a marked decrease in the number and function of peripheral blood helper/inducer (Leu-3+) T lymphocytes, in the spontaneous secretion of interleukin-1 by synovial biopsy specimens, and in the activity of the joint disease. In contrast, levels of IgM, IgA, and IgG rheumatoid factors and C3 concentrations in blood and synovial fluid samples did not change significantly after therapy with total lymphoid irradiation.

In order to test the biocompatibility of wear debris of orthopedic materials, a method has been developed to produce artificial debris of stainless steel, cobalt–chromium alloy, and high-density polyethylene. In this process, called the accelerated rubbing process, two cylindrical blocks of the same alloy were held under normal pressure in triply distilled water. One block remained stationary while the other rotated at ∼4000 rpm. The water with the metal debris was recirculated between the rubbing surfaces. To prepare debris from polyethylene, a stainless steel block was rubbed over a polyethylene block submersed in liquid nitrogen. The shape of the metal debris was granular, whereas the polyethylene debris had a shted-like shape. The size distributions were determined from scanning electron micrographs, and it was found that the particles of the metal debris (stainless steel or cobalt–chrome alloy) ranged in sizes from 0.1–10 μ with 75% of all particles

The functions of the primary ligaments of the human knee have been investigated during anterior, posterior, medial and lateral tibial displacements. The ligaments of in vitro knee specimens have been loaded to large load levels and all three resultant orthogonal components of force and of moment acting on the femur as a result of the applied tibial displacements have been measured. Least squares cubic spline curves fit to the data have been analyzed to determine what percentage of a given applied load is transmitted by each ligament. These curves can also provide data for a computer model of the human leg.